Capture-Collapse Heterocyclization: 1,3-Diazepanes by C-N Reductive Elimination from Rhodacyclopentanones

Article abstract of DOI:10.1021/jacs.6b07046

Rhodacyclopentanones derived from carbonylative C-C activation of cyclopropyl ureas can be "captured" by pendant nucleophiles prior to "collapse" to 1,3-diazepanes. The choice of N-substituent on the cyclopropane unit controls the oxidation level of the product, such that C4-C5 unsaturated or saturated systems can be accessed selectively.

Full text of DOI:10.1021/jacs.6b07046

Communication
pubs.acs.org/JACS
Capture−Collapse Heterocyclization: 1,3-Diazepanes by C−N
Reductive Elimination from Rhodacyclopentanones
Niall G. McCreanor,† Steven Stanton,† and John F. Bower*
School of Chemistry, University of Bristol, Bristol, BS8 1TS, United Kingdom
S
* Supporting Information
family of highly potent HIV protease inhibitors, as exemplified
by DMP 450.2 Other important 1,3-diazepanes include the
structurally intriguing β-lactamase inhibitor MK-7655 devel-
oped by Merck,3 and the mast cell inhibitory alkaloid
(+)-monanchorin.4 The lack of general methods for accessing
1,3-diazepanes reflects wider difficulties in preparing medium
ring systems containing multiple heteroatoms.5 Consequently,
modular catalytic methodologies that address this issue are
likely to be of interest to the pharmaceutical sector.6
ABSTRACT: Rhodacyclopentanones derived from car-
bonylative C−C activation of cyclopropyl ureas can be
“captured” by pendant nucleophiles prior to “collapse” to
1,3-diazepanes. The choice of N-substituent on the
cyclopropane unit controls the oxidation level of the
product, such that C4−C5 unsaturated or saturated
systems can be accessed selectively.
Our laboratory has developed a cycloaddition strategy that
relies on N-directing group controlled insertion of Rh and CO
into the proximal C−C bond of aminocyclopropanes 1
(Scheme 1B).7 The resulting rhodacyclopentanones 2 engage
pendant alkynes or alkenes to provide (3 + 1 + 2)7a,b,d or (7 +
1)7c cycloaddition products. This approach harnesses the strain
embedded within readily prepared (and enantiopure) amino-
cyclopropanes to provide byproduct-free access to complex N-
heterocyclic ring systems. In seeking to expand further the
scope of this catalysis platform, we considered whether
rhodacyclopentanones 2 might be susceptible to attack by
pendant nucleophiles. If successful, this would provide medium
rings 4 via the intermediacy of kinetically accessible bicycles 3,
with a key issue being the scope of the C−Nu reductive
elimination step, a process only known for C−O bond
formation.8 Such catalytic metallacycle “capture−collapse”
sequences have the potential to generate a wide range of
challenging rings containing multiple heteroatoms. In this
report we outline our proof-of-concept studies toward this
broad goal by demonstrating that readily prepared urea-based
systems 5 can be converted directly to substituted 1,3-
diazepanes via previously unknown C−N reductive elimination
from rhodacyclopentanones 7 (Scheme 1C). We also show that
the oxidation level of the product (8 vs 9) can be controlled by
the choice of R1-substituent, thereby providing valuable
additional flexibility to the methodology.
he Biginelli multicomponent reaction provides high
Tversatility for the synthesis of 6-ring cyclic ureas and is
used widely in diversity oriented synthesis.1 However, equally
direct and flexible entries to homologated systems have not
been reported despite the biological significance of the 1,3-
diazepane scaffold (Scheme 1A). This is the core motif in a
Scheme 1
Initial studies examined a range of Rh-catalysts for the
carbonylative cyclization of 5a (Table 1). Under 1 atm of CO,
we found that a cationic Rh(I)-system derived from [Rh-
(cod)2]BARF and triphenylphosphine provided oxidative
product 8a in 82% yield and 20:1 selectivity over the alternate
C4−C5 saturated variant 9a. Notably, neutral Rh(I)-complexes
were completely ineffective and higher CO pressures (e.g., 5
atm) offered no benefits. The presence of an acid cocatalyst
(PhCO2H) was found to have a significant effect, providing
approximately 20% enhancements to the yields of cyclizations
Received: July 8, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.6b07046
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Journal of the American Chemical Society
Communication
a
Table 1. Oxidative Carbonylative Heterocyclizations
Table 2. Redox Neutral Carbonylative Heterocyclizations
a
1
The ratio of 9l−r:8l−r is given in parentheses (determined by H
b
NMR analysis of crude material). Dioxane was used as solvent.
aryl R2-substituents, occurred efficiently to provide targets 9l−r
with 3:1 to 12:1 selectivity over the corresponding C4−C5
unsaturated variants (8l−r).9 The efficient cyclization of tert-
butyl substrate 5o is significant, as this result supports a
carbonyl directed C−C activation pathway (5 to 6 to 7, Scheme
1C). In principle, N-directed C−C bond activation could lead
directly to intermediates 7; however, steric hindrance would
likely render such an initiation mode inefficient for 5o.
a
1
The ratio of 8a−i:9a−i is given in parentheses (determined by H
NMR analysis of crude material).
described throughout this study (vide infra). For clarity, the
numbering system used in Scheme 1C is retained throughout
subsequent discussion: 5 = cyclopropyl substrate; 8 = C4−C5
unsaturated product; 9 = C4−C5 saturated product; letters =
structural variant.
Adaption of the approaches outlined in Tables 1 and 2 to
systems with substitution on the cyclopropane component
revealed interesting and insightful results (vide infra). Trans-
1,2-disubstituted systems 5s−u provided highly selective access
to C4−C5 unsaturated ring systems; the observed regioisomers
8s−u (>15:1 r.r.) are derived from C−C activation of the more
hindered bond b.10 Previous studies involving isolable metalla-
cycles have confirmed that this is the disfavored C−C activation
pathway.7c As expected based on the results in Table 2,
cyclization of 5v, which lacks an N-benzyl substituent on the
aminocyclopropane unit, favored the formation of C4−C5
saturated products (5:2 saturated/unsaturated). In this case,
however, C−C activation regioselectivity was low, providing an
approximately 1:1 ratio of C3:C4 substituted systems 9v and
9v′, which are derived from cleavage of bond b vs bond a,
respectively.11 We have previously established that cis-
disubstituted aminocyclopropanes preferentially undergo direc-
ted C−C bond activation at the more hindered but more
electron-rich bond b.7b However, cyclization of cis-5t and cis-5v
delivered selectively regioisomers 8t′ and 9v′, derived from C−C
activation of less hindered bond a. As expected, in both cases the
oxidation level of the product was controlled by the presence or
absence of an R1-substituent. Bicyclic systems 5w and 5x, which
are not subject to directed C−C activation regiocontrol issues,
cyclized without incident to deliver expected products 8w and
9x in an oxidation level divergent manner.
The results for cis- and trans-disubstituted cyclopropane
systems (Scheme 3A/B) provide important insights into the
mechanism of the processes described here. In these cases,
product regioselectivities are (in general) opposite to what
would be expected based on stoichiometric rhodacyclopenta-
none formations using carbamate protected aminocyclopro-
panes (trans-cyclopropanes: activation of bond a expected,
products from activation of bond b observed; cis-cyclopropanes:
activation of bond b expected, products from activation of bond
a observed).7b,c,12 Initial studies to rationalize this discrepancy
confirmed that N,N,N′-trisubstituted urea directing groups
provide the same C−C activation regioselectivities as carbamate
variants (Scheme 4A). This was done by exposing diastereo-
meric systems trans-5s and cis-5s to the reaction conditions in
The scope of the process is outlined in Table 1. In the
majority of cases cyclization was efficient, generating the target
C4−C5 unsaturated systems with high selectivity (5:1 to 24:1)
over their saturated congeners. The protocol tolerates a wide
range of aryl or alkyl substituents at R1. Even potentially
sensitive functionality survives, such as the ester of 5h and the
cyclopropylmethyl group of 5i; the latter highlights the
exquisite selectivity of the initial C−C activation step. The
tolerance of the process to the R2 group shows greater variance:
alkyl groups, including sterically encumbered variants (e.g., 5d),
performed well but N-aryl groups were less effective, perhaps
due to the lower nucleophilicity of the nitrogen center. The
ability to access unsaturated products efficiently opens up
further opportunities for methodology design (Scheme 2). For
Scheme 2. Serial Rh-Catalyzed and Brønsted Acid Promoted
Cyclizations
example, 5j/k, which are equipped with pendant (hetero)aryl
groups underwent Rh-catalyzed heterocyclization and subse-
quent iminium ion triggered ring closure to provide complex
tricyclic systems 10j/k, as confirmed by single crystal X-ray
diffraction.
The processes outlined in Table 1 provide efficient oxidative
access to systems possessing C4−C5 unsaturation. If redox
neutral processes could be promoted, then complementary
access to C4−C5 saturated systems would also be possible,
allowing an unusual oxidation level divergent entry to the target
diazepanes. In the event, we observed that high selectivity for
this pathway can be achieved using systems where R1 = H
(Table 2). Under conditions similar to those outlined in Table
2, cyclization of 5l−r, which encompasses a range of alkyl or
B
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Journal of the American Chemical Society
Communication
Scheme 3
Scheme 4
a
The ratio of 8:9 is given in parentheses (major product depicted;
b
ratio determined by 1H NMR analysis of crude material). [Rh-
(cod)2]BF4 (7.5−10 mol %) used as precatalyst. The minor
component (8x) had C3−C4 unsaturation.
c
the absence of CO; decomposition products generated from
the putative rhodacyclobutane intermediate (not depicted)
indicate the kinetically favored site of C−C oxidative
addition.13 Trans-disubstituted cyclopropane trans-5s gener-
ated selectively alkene 11b, which is derived from C−C
activation of bond a, whereas cis-disubstituted system cis-5s
provided predominantly 11a (11:1 11a:11b), via preferential
activation of bond b. Thus, in both cases, C−C activation
regioselectivity is in line with previous stoichiometric studies7b,c
but opposite to that observed in Scheme 3A/B.
We have shown in earlier work that directed rhodacyclo-
pentanone formation is (highly) reversible when cationic Rh-
systems are employed.7b,c As such, product regioselectivity can
be controlled by the facility of processes other than the initial
directed C−C activation step. This type of Curtin−Hammett
scenario (i.e., reversible formation of 7 from 5, see Scheme 1C)
underpins proposed mechanisms for the processes described
here. For trans-disubstituted systems, rhodacyclopentanone
formation via cleavage of bond a is preferred leading to
metallacycle IA (Scheme 4B). However, subsequent C−N
reductive elimination to IIA is slow because of the developing
steric clash between the Rh-center and the R3-substituent.
Accordingly, reprotonation of nitrogen, retro-carbonylation,
and C−C reductive elimination regenerate the cyclopropane
and enable equilibration to disfavored metallacycle IB. Here,
C−N reductive elimination is likely more facile because the Rh-
center of IIB is further from the R3-substituent (cf. IIA, 1,2- vs
1,3-relationship); consequently, the C3-substituted product is
generated selectively. For trans-5v, where R1 = H, steric
constraints for IA to IIA may, to a certain extent, be alleviated,
such that progression to the 4-substituted product becomes
competitive and low regioselectivity is observed.14 A similar but
distinct selectivity model is proposed for cis-disubstituted
systems (Scheme 4C). Here, rhodacyclopentanone formation
via bond b is favored leading to metallacycle ID; however, C−
N reductive elimination from this intermediate may be slow
due to developing steric clashes between the N−R2 group and
the R3-substituent. As before, reversible metallacycle formation
C
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Journal of the American Chemical Society
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allows equilibration to IC, where this steric impediment is
alleviated en route to the C4-substituted product. Thus, we
suggest that for both systems the unexpected product
regioselectivities are determined by the facility of C−N
reductive elimination rather than C−C activation.15
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proton released by conversion of 6 to 7 (see Scheme 1C).
In summary, we demonstrate an approach to substituted 1,3-
diazepanes as proof-of-concept for a general metallacycle
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will allow the generation of a range of medium ring systems
containing multiple heteroatoms; studies toward this broad goal
are underway.18 The findings described here enhance
significantly the scope of the catalysis platform outlined in
Scheme 1B (1 to 2), opening up numerous avenues for further
exploration, while at the same time adding to the wider and
emerging area of rhodacyclopentanone-based catalysis.7,8,19
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(9) A one-pot synthesis of 9l (57% yield, 6:1 saturated:unsaturated)
from cyclopropylamine is given in the Supporting Information (SI).
(10) Cyclization of (S,S)-trans-5s (>98% ee) provided (S)-8s in
>98% ee (see the SI).
(11) Replacement of the n-butyl group with methyl or cyclohexyl
substituents gave analogous results (see the SI).
(12) The relative stereochemistry of 1,2-disubstituted cyclopropane
substrates was determined using a combination of X-ray crystallo-
graphic analysis (trans-5s) and NOE experiments.
(13) Similar results were obtained in the presence of PhCO2H (15
mol%). The SI details analogous experiments for carbamate protected
systems, confirming that C−C activation selectivity is the same in the
absence and presence of CO.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b07046.
Experimental details, characterization data (PDF)
Crystallographic data (CIF, CIF, CIF)
(14) For the conversion of trans-5v to 8v′, β-hydride elimination
presumably occurs via N6-H.
(15) Alternate explanations cannot be discounted on the basis of
available data. For example, the steric effects of the R3-group may
result in slow formation of ID, rather than slow reductive elimination
from this intermediate.
(16) The suggestion that the alkene dissociates assumes stereo-
specific protodemetalation.
AUTHOR INFORMATION
■
Corresponding Author
*john.bower@bris.ac.uk
Author Contributions
(17) Gridnev, I. D.; Higashi, N.; Asakura, K.; Imamoto, T. J. Am.
Chem. Soc. 2000, 122, 7183.
†N.G.McC. and S.S. contributed equally.
(18) By the strictest (IUPAC) definition, 7-ring systems are not
classed as medium rings. However, the chemistry described here is an
important conceptual stepping stone towards this goal because
conventional 7-ring cyclizations are, in terms of kinetics, significantly
more demanding than 5- or 6-ring variants: Illuminati, G.; Mandolini,
L.; Masci, B. J. Am. Chem. Soc. 1975, 97, 4960.
(19) (a) Review: Shaw, M. H.; Bower, J. F. Chem. Commun. 2016,
DOI: 10.1039/c6cc04359c. Selected recent contributions: (b) Zhou,
X.; Dong, G. J. Am. Chem. Soc. 2015, 137, 13715. (c) Ko, H. M.; Dong,
G. Nat. Chem. 2014, 6, 739. (d) Souillart, L.; Parker, E.; Cramer, N.
Angew. Chem., Int. Ed. 2014, 53, 3001. (e) Souillart, L.; Cramer, N.
Angew. Chem., Int. Ed. 2014, 53, 9640. (f) Matsuda, T.; Tsuboi, T.;
Murakami, M. J. Am. Chem. Soc. 2007, 129, 12596.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
European Research Council via the EU’s Horizon 2020
Programme (ERC grant 639594 CatHet). Bristol Chemical
Synthesis Centre for Doctoral Training (EPSRC grant EP/
G036764/1) for a studentship (N.G.M). University of Bristol
X-ray crystallographic service for analysis of trans-5s, 10j, and
10k. Royal Society for a University Research Fellowship
(J.F.B.).
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DOI: 10.1021/jacs.6b07046
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX